Compounds having CRTH2 antagonist activity

ABSTRACT

Compounds of general formula (II) 
                         
wherein
     W is chloro or fluoro;   R 1  is phenyl optionally substituted with one or more substituents, selected from halo, —CN, —C 1 -C 6  alkyl, —SOR 3 , —SO 2 R 3 , —SO 2 N(R 2 ) 2 , —N(R 2 ) 2 , —NR 2 C(O)R 3 , —CO 2 R 2 , —CONR 2 R 3 , —NO 2 , —OR 2 , —SR 2 , —O(CH 2 ) p OR 2 , or —O(CH 2 ) p O(CH 2 ) q OR 2  wherein
       each R 2  is independently hydrogen, —C 1 -C 6  alkyl, —C 3 -C 8  cycloalkyl, aryl or heteroaryl;   each R 3  is independently, —C 1 -C 6  alkyl, —C 3 -C 8  cycloalkyl, aryl or heteroaryl;   p and q are each independently an integer from 1 to 3; and   
       R 4  is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkyl substituted with aryl, aryl, (CH 2 ) m OC(═O)C 1 -C 6 alkyl, ((CH 2 ) m O) n CH 2 CH 2 X, (CH 2 ) m N(R 5 ) 2  or CH((CH 2 ) m O(C═O)R 6 ) 2 ;
       m is 1 or 2;   n is 1-4;   X is OR 5  or N(R 5 ) 2 ;   R 5  is hydrogen or methyl; and   R 6  is C 1 -C 18  alkyl;
 
and their pharmaceutically acceptable salts, hydrates, solvates, complexes or prodrugs are useful in orally administrable compositions for the treatment of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis.

The present invention relates to compounds which are useful aspharmaceuticals, to methods for preparing these compounds, compositionscontaining them and their use in the treatment and prevention ofallergic diseases such as asthma, allergic rhinitis and atopicdermatitis and other inflammatory diseases mediated by prostaglandin D₂(PGD₂) or other agonists acting at the CRTH2 receptor on cells includingeosinophils, basophils and Th2 lymphocytes.

PGD₂ is an eicosanoid, a class of chemical mediator synthesised by cellsin response to local tissue damage, normal stimuli or hormonal stimulior via cellular activation pathways. Eicosanoids bind to specific cellsurface receptors on a wide variety of tissues throughout the body andmediate various effects in these tissues. PGD₂ is known to be producedby mast cells, macrophages and Th2 lymphocytes and has been detected inhigh concentrations in the airways of asthmatic patients challenged withantigen (Murray et al., (1986), N. Engl. J. Med. 315: 800-804).Instillation of PGD₂ into airways can provoke many features of theasthmatic response including bronchoconstriction (Hardy et al., (1984)N.Engl. J. Med. 311: 209-213; Sampson et al., (1997) Thorax 52: 513-518)and eosinophil accumulation (Emery et al., (1989) J. Appl. Physiol. 67:959-962).

The potential of exogenously applied PGD₂ to induce inflammatoryresponses has been confirmed by the use of transgenic miceoverexpressing human PGD₂ synthase which exhibit exaggeratedeosinophilic lung inflammation and Th2 cytokine production in responseto antigen (Fujitani et al., (2002) J. Immunol. 168: 443-449).

The first receptor specific for PGD₂ to be discovered was the DPreceptor which is linked to elevation of the intracellular levels ofcAMP. However, PGD₂ is thought to mediate much of its proinflammatoryactivity through interaction with a G protein-coupled receptor termedCRTH2 (chemoattractant receptor-homologous molecule expressed on Th2cells) which is expressed by Th2 lymphocytes, eosinophils and basophils(Hirai et al., (2001) J. Exp. Med. 193: 255-261, and EP0851030 andEP-A-1211513 and Bauer et al., EP-A-1170594). It seems clear that theeffect of PGD₂ on the activation of Th2 lymphocytes and eosinophils ismediated through CRTH2 since the selective CRTH2 agonists 13,14dihydro-15-keto-PGD₂ (DK-PGD₂) and 15R-methyl-PGD₂ can elicit thisresponse and the effects of PGD₂ are blocked by an anti-CRTH2 antibody(Hirai et al., 2001; Monneret et al., (2003) J. Pharmacol. Exp. Ther.304: 349-355). In contrast, the selective DP agonist BW245C does notpromote migration of Th2 lymphocytes or eosinophils (Hirai et al., 2001;Gervais et al., (2001) J. Allergy Clin. Immunol. 108: 982-988). Based onthis evidence, antagonising PGD₂ at the CRTH2 receptor is an attractiveapproach to treat the inflammatory component of Th2-dependent allergicdiseases such as asthma, allergic rhinitis and atopic dermatitis.

EP-A-1170594 suggests that the method to which it relates can be used toidentify compounds which are of use in the treatment of allergic asthma,atopic dermatitis, allergic rhinitis, autoimmune, reperfusion injury anda number of inflammatory conditions, all of which are mediated by theaction of PGD₂ or other agonists at the CRTH2 receptor.

Compounds which bind to CRTH2 are taught in WO-A-03066046 andWO-A-03066047. These compounds are not new but were first disclosed,along with similar compounds, in GB 1356834, GB 1407658 and GB 1460348,where they were said to have anti-inflammatory, analgesic andantipyretic activity. WO-A-03066046 and WO-A-03066047 teach that thecompounds to which they relate are modulators of CRTH2 receptor activityand are therefore of use in the treatment or prevention of obstructiveairway diseases such as asthma, chronic obstructive pulmonary disease(COPD) and a number of other diseases including various conditions ofbones and joints, skin and eyes, GI tract, central and peripheralnervous system and other tissues as well as allograft rejection. Thesecompounds are all indole derivatives with an acetic acid substituent atthe 3-position of the indole ring.

PL 65781 and JP 43-24418 also relate to indole-3 acetic acid derivativeswhich are similar in structure to indomethacin and, like indomethacin,are said to have anti-inflammatory and antipyretic activity. Thus,although this may not have been appreciated at the time when thesedocuments were published, the compounds they describe are COXinhibitors, an activity which is quite different from that of thecompounds of the present invention. Indeed, COX inhibitors arecontraindicated in the treatment of many of the diseases and conditions,for example asthma and inflammatory bowel disease for which thecompounds of the present invention are useful, although they maysometimes be used to treat arthritic conditions.

There is further prior art which relates to indole-1-acetic acidcompounds, although these are not described as CRTH2 antagonists. Forexample WO-A-9950268, WO-A-0032180, WO-A-0151849 and WO-A-0164205 allrelate to compounds which are indole-1-acetic acid derivatives but thesecompounds are said to be aldose reductase inhibitors useful in thetreatment of diabetes mellitus (WO-A-9950268, WO-A-0032180 andWO-A-0164205) or hypouricemic agents (WO-A-0151849). There is nosuggestion in any of these documents that the compounds would be usefulfor the treatment of diseases and conditions mediated by PGD₂ or otherCRTH2 receptor agonists.

U.S. Pat. No. 4,363,912 relates to indole-1-alkyl carboxylic acidderivatives (including indole-1-acetic acid analogues) which are said tobe inhibitors of thromboxane synthetase and to be useful in thetreatment of conditions such as thrombosis, ischaemic heart disease andstroke. The compounds have an unsubstituted 3-pyridyl or 4-pyridylsubstituent in an equivalent position to the pyridyl group of generalformula (I). Evaluation of the closest analogue(5-fluoro-2-methyl-3-(pyridin-3-ylmethyl)-indol-1-yl)-acetic acid) thatfalls within the claims of U.S. Pat. No. 4,363,912 to the compounds ofthe present invention indicates that it is significantly less active asa CRTH2 antagonist than the compounds of the present invention. Incontrast to the compounds of the present invention (which are allindole-1-acetic acid derivatives) the preferred compounds within U.S.Pat. No. 4,363,912 are 3-(indol-1-yl)-propionic acid derivatives.

WO-A-9603376 relates to compounds which are said to be sPLA₂ inhibitorswhich are useful in the treatment of bronchial asthma and allergicrhinitis. These compounds all have amide or hydrazide substituents inplace of the carboxylic acid derivative of the compounds of the presentinvention.

JP 2001247570 relates to a method of producing a 3-benzothiazolylmethylindole acetic acid, which is said to be an aldose reductase inhibitor.

U.S. Pat. No. 4,859,692 relates to compounds which are said to beleukotriene antagonists useful in the treatment of conditions such asasthma, hay fever and allergic rhinitis as well as certain inflammatoryconditions such as bronchitis, atopic and ectopic eczema. Some of thecompounds of this document are indole-1-acetic acids but the sameauthors, in J. Med. Chem., 33, 1781-1790 (1990), teach that compoundswith an acetic acid group on the indole nitrogen do not have significantpeptidoleukotriene activity.

U.S. Pat. No. 4,273,782 is directed to indole-1-acetic acid derivativeswhich are said to be useful in the treatment of conditions such asthrombosis, ischaemic heart disease, stroke, transient ischaemic attack,migraine and the vascular complications of diabetes. There is no mentionin the document of conditions mediated by the action of PGD₂ or otheragonists at the CRTH2 receptor.

U.S. Pat. No. 3,557,142 relates to 3-substituted-1-indole carboxylicacids and esters which are said to be useful in the treatment ofinflammatory conditions.

WO-A-03/097598 relates to compounds which are CRTH2 receptorantagonists. They do not have an aryl substituent at the indole-3position.

Cross et al., J. Med. Chem. 29, 342-346 (1986) relates to a process forpreparing indole-1-acetic acid derivatives from the correspondingesters. The compounds to which it relates are said to be inhibitors ofthromboxane synthetase.

EP-A-0539117 relates to indole-1-acetic acid derivatives which areleukotriene antagonists.

US 2003/0153751 relates to indole-1-acetic acid derivatives which aresPLA₂ inhibitors. However, all of the exemplified compounds have bulkysubstituents at the 2- and 5-positions of the indole system and aretherefore very different from the compounds of the present invention.

US 2004/011648 discloses indole-1-acetic acid derivatives which areinhibitors of PAI-1. There is no suggestion that the compounds mighthave CRTH2 antagonist activity.

WO 2004/058164 relates to compounds which are said to be asthma andallergic inflammation modulators. The only compounds for which activityis demonstrated are entirely different in structure from theindole-1-acetic acid derivatives of the present invention.

Compounds which bind to the CRTH2 receptor are disclosed inWO-A-03/097042 and WO-A-03/097598. These compounds are indole aceticacids but in WO-A-03/097042 the indole system is fused at the 2-3positions to a 5-7 membered carbocyclic ring. In WO-A-03/097598 there isa pyrrolidine group at the indole 3-position.

WO-A-03/101981, WO-A-03/101961 and WO-A-2004/007451 all relate toindole-1-acetic acid derivatives which are said to be CRTH2 antagonistsbut which differ in structure from the compounds of general formula (I)because there is no spacer or an —S— or —SO₂— group attached to theindole 3-position in place of the CH₂ group of the compounds of thepresent invention as described below.

WO-A-2005/019171 also describes indole-1-acetic acid derivatives whichare said to be CRTH2 antagonists and which are said to be useful for thetreatment of various respiratory diseases. These compounds all have asubstituent which is linked to the indole-3 position by an oxygenspacer.

WO-A-2005/094816 again describes indole-1-acetic acid compounds, thistime with an aliphatic substituent at the 3-position of the indole ring.The compounds are said to be CRTH2 antagonists.

WO-A-2006/034419 relates to CRTH2 antagonist indole compounds which havea heterocyclic or heteroaryl substituent directly linked to the3-position of the indole ring system.

In our earlier application, WO-A-2005/044260, we describe compoundswhich are antagonists of PGD₂ at the CRTH2 receptor. These compounds areindole-1-acetic acid derivatives substituted at the 3-position with agroup CR⁸R⁹, wherein R⁹ is hydrogen or alkyl and R⁸ is an aryl groupwhich may be substituted with one or more substituents. The compoundsdescribed in this document are potent antagonists in vitro of PGD₂ atthe CRTH2 receptor. However, we have found that when tested in vivo, thepharmacokinetic profile of some compounds is not optimal and theirpotency in the whole blood eosinophil shape change test, which gives anindication of the likely in vivo activity of the compounds, is oftensomewhat less than might have been expected from the in vitro bindingresults.

In another of our earlier applications, WO2006/095183, theindole-1-acetic acid derivatives are substituted at the 3-position witha 1-benzenesulfonyl-1H-pyrrol-2-ylmethyl group, where the phenyl groupof the benzenesulfonyl moiety may be substituted. These compounds areextremely active CRTH2 antagonists but are rapidly metabolised asdetermined by incubation with human microsome preparations.

Our application WO2008/012511 also relates to CRTH2 antagonistcompounds, this time to indole-1-acetic acid derivatives substituted atthe 3-position with a 2-phenylsulfonylbenzyl group. It was found thatthe position of the phenylsulfonyl substituent had a significant effecton both the activity of the compounds and their pharmacokinetic profile.

The present invention relate to pyridyl analogues of the compounds ofWO2008/012511. These compounds do not suffer from the metabolicstability disadvantages of the compounds of WO2006/095183 and,surprisingly, it has been found that specific pyridyl regioisomers andsubstitution thereof gives rise to an optimal balance of potency andpharmacokinetic properties. Specifically it has been found that theintroduction of a phenyl sulfonyl substituent onto the 2-position of thepyridin-3-yl regioisomer provides compounds with good potency in afunctional in vitro assay together with good pharmacokinetics in vivo.That this combination should result in a highly beneficial combinationof properties is not obvious and is not taught by the literature andpatent applications relating to CRTH2 antagonists. It is particularlysurprising that the 2-benzenesulfonyl-pyridin-3-yl compounds are potentand specific antagonists of the CRTH2 receptor both in a receptorbinding assay and in a functional in vitro assay as we have found thatthe 3-benzenesulfonyl-pyridin-2-yl analogue is significantly less potentand that the 3-benzenesulfonyl-pyridin-4-yl analogue exhibits loweractivity in the functional in vitro assay than might be expected fromits receptor binding activity. It therefore appears that the position ofthe pyridyl nitrogen is particularly significant in the compounds of theinvention.

The present invention therefore relates to novel compounds which bind tothe CRTH2 receptor and which are therefore useful in the treatment ofdiseases and conditions mediated by the activity of PGD₂ at the CRTH2receptor.

In the present invention there is provided a compound of general formula(I)

wherein

-   W is chloro or fluoro;-   R¹ is phenyl optionally substituted with one or more substituents    selected from halo, —CN, —C₁-C₆ alkyl, —SOR³, —SO₂R³, —SO₂N(R²)₂,    —N(R²)₂, —NR²C(O)R³, —CO₂R², —CONR²R³, —NO₂, —OR², —SR²,    —O(CH₂)_(p)OR², and —O(CH₂)_(p)O(CH₂)_(q)OR² wherein    -   each R² is independently hydrogen, —C₁-C₆ alkyl, —C₃-C₈        cycloalkyl, aryl or heteroaryl;    -   each R³ is independently, —C₁-C₆ alkyl, —C₃-C₈ cycloalkyl, aryl        or heteroaryl;    -   p and q are each independently an integer from 1 to 3;        or a pharmaceutically acceptable salt, hydrate, solvate, complex        or prodrug thereof.

The compounds of general formula (I) are antagonists at the CRTH2receptor and are useful in the treatment of conditions which aremediated by PGD₂ or other agonists binding to CRTH2. These includeallergic diseases, asthmatic conditions and inflammatory diseases,examples of which are asthma, including allergic asthma, bronchialasthma, exacerbations of asthma and related allergic diseases caused byviral infection, particularly those exacerbations caused by rhinovirusand respiratory syncytial virus intrinsic, extrinsic, exercise-induced,drug-induced and dust-induced asthma, treatment of cough, includingchronic cough associated with inflammatory and secretory conditions ofthe airways and iatrogenic cough, acute and chronic rhinitis, includingrhinitis medicamentosa, vasomotor rhinitis, perennial allergic rhinitis,seasonal allergic rhinitis, nasal polyposis, acute viral infectionincluding common cold, infection due to respiratory syncytial virus,influenza, coronavirus and adenovirus, atopic dermatitis, contacthypersensitivity (including contact dermatitis), eczematous dermatitis,phyto dermatitis, photo dermatitis, sebhorroeic dermatitis, dermatitisherpetiformis, lichen planus, lichen sclerosis et atrophica, pyodermagangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus,pemphigoid, epidermolysis bullosa urticaria, angioedema, vasculitides,toxic erythemas, cutaneous eosinophilias, alopecia greata, male-patternbaldness, Sweet's syndrome, Weber-Christian syndrome, erythemamultiforme, cellulitis, panniculitis, cutaneous lymphomas, non-melanomaskin cancer and other dysplastic lesions; blepharitis conjunctivitis,especially allergic conjunctivitis, anterior and posterior uveitis,choroiditis, autoimmune, degenerative or inflammatory disordersaffecting the retina, ophthalmitis; bronchitis, including infectious andeosinophilic bronchitis, emphysema, bronchiectasis, farmer's lung,hypersensitivity pneumonitis, idiopathic interstitial pneumonias,complications of lung transplantation, vasculitic and thromboticdisorders of the lung vasculature, pulmonary hypertension, foodallergies, gingivitis, glossitis, periodontitis, oesophagitis includingreflux, eosinophilic gastroenteritis, proctitis, pruris ani, celiacdisease, food-related allergies, inflammatory bowel disease, ulcerativecolitis and Crohn's disease, mastocytosis and also other CRTH2-mediateddiseases, for example autoimmune diseases such as hyper IgE syndrome,Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetesmellitus, idiopathic thrombocytopaenic purpura, eosinophilic paschiitis,antiphospholipid syndrome and systemic lupus erythematosus, AIDS,leprosy, Sezary syndrome, paraneoplastic syndrome, mixed andundifferentiated connective tissue diseases, inflammatory myopathiesincluding dermatomyositis and polymyositis, polymalgia rheumatica,juvenile arthritis, rheumatic fever, vasculitides including giant cellarteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritisnodosa, microscopic polyarteritis, temporal arteritis, myastheniagravis, acute and chronic pain, neuropathic pain syndromes, central andperipheral nervous system complications of malignant, infectious orautoimmune processes, low back pain, familial Mediterranean Fever,Muckle-Wells syndrome, Familial Hibernian fever, Kikuchi disease,psoriasis, acne, multiple sclerosis, allograft rejection, reperfusioninjury, chronic obstructive pulmonary disease, as well as rheumatoidarthritis, Still's disease, ankylosing spondylitis, reactive arthritis,undifferentiated spondarthropathy, psoriatic arthritis, septic arthritisand other infection-related arthopathies and bone disorders andosteoarthritis; acute and chronic crystal-induced synovitis includingurate gout, calcium pyrophosphate deposition disease, calcium paptiterelated tendon syndrome and synovial inflammation, Behcet's disease,primary and secondary Sjogren's syndrome systemic sclerosis and limitedscleroderma; hepatitis, cirrhosis of the liver, cholecystitis,pancreatitis, nephritis, nephritic syndrome, cystitis and Runner'sulcer, acute and chronic urethritis, prostatitis, epididymitis,oophoritis, salpingitis, vulvo-vaginitis, Peyronie's disease, erectiledysfunction, Alzheimer's disease and other dementing disorders;pericarditis, myocarditis, inflammatory and auto-immune cardiomyopathiesincluding myocardial sarcoid, ischaemic reperfusion injuries,endocarditis, valvulitis, aortitis, phlebitis, thrombosis, treatment ofcommon cancers and fibrotic conditions such as idiopathic pulmonaryfibrosis including cryptogenic fibrosing alveolitis, keloids, excessivefibrotic scarring/adhesions post surgery, liver fibrosis including thatassociated with hepatitis B and C, uterine fibroids, sarcoidosis,including neurosarcoidosis, scleroderma, kidney fibrosis resulting fromdiabetes, fibrosis associated with RA, atherosclerosis, includingcerebral atherosclerosis, vasculitis, myocardial fibrosis resulting frommyocardial infarction, cystic fibrosis, restenosis, systemic sclerosis,Dupuytren's disease, fibrosis complicating anti-neoplastic therapy andchronic infection including tuberculosis and aspergillosis and otherfungal infections, CNS fibrosis following stroke or the promotion ofhealing without fibrotic scarring.

The improved potency in the whole blood eosinophil shape change test andpharmacokinetic profile of the compounds of general formula (I) isparticularly surprising since some of the compounds of WO-A-2005/044260,which are closest in structure to the compounds of general formula (I)do not have these advantageous properties. In particular, the compoundof Example 17 of WO-A-2005/044260 is similar to the compounds of thepresent invention and might have been expected to have similarproperties. However, in in vivo experiments carried out in the dog, thereplacement of the 4-methylsulfonylbenzyl group in Example 17 ofWO-A-2005/044260 with the 2-(benzenesulfonyl)pyridine-3-ylmethyl groupin the compounds of formula (I) has a significant effect on thepharmacokinetics of the compounds because when Compound 17 ofWO-A-2005/044260 is administered orally, its pharmacokinetic profile invivo is less favourable than that of the compounds of general formula(I).

In addition for many of the compounds of WO-A-2005/044260, we have foundthat their in vitro whole blood eosinophil shape change activity isoften less than might have been expected from their in vitro activity asmeasured by radioligand binding experiments to the CRTH2 receptor.

Furthermore, the improvement in activity is very specific to the groupof compounds of general formula (I). Compounds which are even moreclosely related to the compounds specifically disclosed inWO-A-2005/044260 do not have such favourable properties. For example,the analogues of general formula (I) in which the SO₂R group is not at aposition on the pyridine ring adjacent the linking methylene moietywhich is joined to the 3-position of the indolyl scaffold are lessactive in in vitro whole blood eosinophil shape change tests.

In the present specification “C₁-C₆ alkyl” refers to a straight orbranched saturated hydrocarbon chain having one to six carbon atoms andoptionally substituted with one or more halo substituents and/or withone or more C₃-C₈ cycloalkyl groups. Examples include methyl, ethyl,n-propyl, isopropyl, t-butyl, n-hexyl, trifluoromethyl, 2-chloroethyl,methylenecyclopropyl, methylenecyclobutyl, methylenecyclobutyl andmethylenecyclopentyl.

The term “C₁-C₁₈ alkyl” has a similar meaning to the above except thatit refers to a straight or branched saturated hydrocarbon chain havingone to eighteen carbon atoms.

In the present specification “C₃-C₈ cycloalkyl” refers to a saturatedcarbocyclic group having three to eight ring atoms and optionallysubstituted with one or more halo substituents. Examples includecyclopropyl, cyclopentyl, cyclohexyl and 4-fluorocyclohexyl.

In the present specification, “halo” refers to fluoro, chloro, bromo oriodo.

The term “aryl” in the context of the present specification refer to aring system with aromatic character having from 5 to 14 ring carbonatoms and containing up to three rings. Where an aryl group containsmore than one ring, not all rings must be fully aromatic in character.Examples of aromatic moieties are benzene, naphthalene, indane andindene.

The term “heteroaryl” in the context of the specification refer to aring system with aromatic character having from 5 to 14 ring atoms, atleast one of which is a heteroatom selected from N, O and S, andcontaining up to three rings. Where a heteroaryl group contains morethan one ring, not all rings must be fully aromatic in character.Examples of heteroaryl groups include pyridine, pyrimidine, indole,benzofuran, benzimidazole and indolene.

General formula (I) as shown above is intended to include all isotopicvariants, for example the hydrogen atoms of the molecule can be ¹H, ²Hor ³H and the carbon atoms can be ¹²C or ¹⁴C.

Appropriate pharmaceutically and veterinarily acceptable salts of thecompounds of general formulae (I) include basic addition salts such assodium, potassium, calcium, aluminium, zinc, magnesium and other metalsalts as well as choline, diethanolamine, ethanolamine, ethyl diamine,megulmine and other well known basic addition salts as summarised inPaulekuhn et al., (2007) J. Med. Chem. 50: 6665-6672 and/or known tothose skilled in the art.

Salts which are not pharmaceutically or veterinarily acceptable maystill be valuable as intermediates.

Prodrugs are any covalently bonded compounds which release the activeparent drug according to general formula (I) in vivo. Examples ofprodrugs include alkyl esters of the compounds of general formula (I),for example the esters of general formula (II) below.

In particularly suitable compounds of general formula (I), W is a fluorosubstituent and the phenyl group R¹ is unsubstituted or is substitutedwith a single halo substituent, usually fluoro or chloro, which isgenerally at the 4-position of the phenyl group R¹.

Particularly active compounds of the present invention are:

-   (3-{[2-(Benzenesulfonyl)pyridin-3-yl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic    acid;-   [5-Fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic    acid;-   [3-({2-[(4-Chlorobenzene)sulfonyl]pyridin-3-yl}methyl)-5-fluoro-2-methylindol-1-yl]-acetic    acid;    or the C₁-C₆ alkyl, aryl, (CH₂)_(m)OC(═O)C₁-C₆alkyl,    ((CH₂)_(m)O)_(n)CH₂CH₂X, (CH₂)_(m)N(R⁵)₂ or CH((CH₂)_(m)O(C═O)R⁶)₂    ester thereof;    -   m is 1 or 2;    -   n is 1-4;    -   X is OR⁵ or N(R⁵)₂;    -   R⁵ is hydrogen or methyl;    -   R⁶ is C₁-C₁₈ alkyl.

In a further aspect of the present invention, there is provided acompound of general formula (II):

wherein W and R¹ are as defined for general formula (I); and

R⁴ is C₁-C₆ alkyl, C₁-C₆ alkyl substituted with aryl, aryl,(CH₂)_(m)OC(═O)C₁-C₆alkyl, ((CH₂)_(m)O)_(n)CH₂CH₂X, (CH₂)_(m)N(R⁵)₂ orCH((CH₂)_(m)O(C═O)R⁶)₂;

-   -   m is 1 or 2;    -   n is 1-4;    -   X is OR⁵ or N(R⁵)₂;    -   R⁵ is hydrogen or methyl;    -   R⁶ is C₁-C₁₈ alkyl;        or a pharmaceutically acceptable salt, hydrate, solvate, complex        or prodrug thereof.

Compounds of general formula (II) are novel and may be used as prodrugsfor compounds of general formula (I). When the compound of generalformula (II) acts as a prodrug, it is later transformed to the drug bythe action of an esterase in the blood or in a tissue of the patient.

Examples of particularly suitable R⁴ groups when the compound of generalformula (II) is used as a prodrug include methyl, ethyl, propyl, phenyl,—O(CH₂)₂O(CH₂)₂OR⁵, —O(CH₂)₂O(CH₂)₂O(CH₂)₂OR⁵, —O(CH₂)₂O(CH₂)₂NR⁵ ₂,—O(CH₂)₂O(CH₂)₂O(CH₂)₂NR⁵ ₂, —CH₂OC(═O)tBu, —CH₂CH₂N(Me)₂, —CH₂CH₂NH₂ or—CH(CH₂O(C═O)R⁶)₂ wherein R⁵ and R⁶ are as defined above.

In addition to their use as prodrugs, compounds of formula (II) whereinR⁴ is C₁-C₆ alkyl or benzyl may be used in a process for the preparationof a compound of general formula (I), the process comprising reactingthe compound of general formula (II) with a base such as sodiumhydroxide or lithium hydroxide. The reaction may take place in anaqueous solvent or an organic solvent or a mixture of the two. A typicalsolvent used for the reaction is a mixture of tetrahydrofuran and water.

Compounds of general formula (II) may be prepared from compounds ofgeneral formula (III):

wherein W is as defined in general formula (I) and R⁴ is as defined ingeneral formula (II); by reaction with an aldehyde of general formula(IV):

wherein R¹ is as defined for general formula (I). The reaction may becarried out in the presence of trimethylsilyltriflate (TMSOTf) in a nonpolar organic solvent and at reduced temperature, for example −5 to 10°C., typically 0° C. The intermediate product is then reduced, forexample with a trialkylsilane such as triethylsilane.

Procedures for the preparation of compounds of general formula (III) areknown to those skilled in the art and in general involve alkylation ofthe 5-halo-indole derivative at the 1-position with analpha-bromoacetate derivative or related alkylating agent. 5-Halo-indolederivatives are readily available or may be prepared by known methods.

Compounds of general formula (IV) may be prepared by the reaction of acompound of general formula (V):

wherein X is a leaving group such as halo, especially fluoro or chloro;with a compound of general formula (VI):R¹—SO₂Na  (VI)wherein R¹ is as defined for general formula (I).

The reaction may be carried out in a polar organic solvent such as DMSOat elevated temperature, typically reflux temperature for a prolongedperiod, for example 48 to 120 hours.

Compounds of general formula (V) and (VI) are commercially available.

Compounds of general formula (I) are CRTH2 receptor antagonists andcompounds of general formula (II) are prodrugs for compounds of generalformula (I). Compounds of general formulae (I) and (II) are thereforeuseful in a method for the treatment of diseases and conditions mediatedby PGD₂ or other agonists at the CRTH2 receptor, the method comprisingadministering to a patient in need of such treatment a suitable amountof a compound of general formula (I) or (II).

In a third aspect of the invention, there is provided a compound ofgeneral formula (I) or (II) for use in medicine, particularly for use inthe treatment or prevention of diseases and conditions mediated by PGD₂or other CRTH2 receptor agonists.

Furthermore, there is also provided the use of a compound of generalformula (I) or (II) in the preparation of an agent for the treatment orprevention of diseases and conditions mediated by CRTH2 receptoragonists, particularly PGD₂.

As mentioned above, such diseases and conditions include allergicdiseases, asthmatic conditions and inflammatory diseases, examples ofwhich are asthma, including allergic asthma, bronchial asthma,intrinsic, extrinsic, exercise-induced, drug-induced and dust-inducedasthma, treatment of cough, including chronic cough associated withinflammatory and secretory conditions of the airways and iatrogeniccough, acute and chronic rhinitis, including rhinitis medicamentosa,vasomotor rhinitis, perennial allergic rhinitis, seasonal allergicrhinitis, nasal polyposis, acute viral infection including common cold,infection due to respiratory syncytial virus, influenza, coronavirus andadenovirus, atopic dermatitis, contact hypersensitivity (includingcontact dermatitis), eczematous dermatitis, phyto dermatitis, photodermatitis, sebhorroeic dermatitis, dermatitis herpetiformis, lichenplanus, lichen sclerosis et atrophica, pyoderma gangrenosum, skinsarcoid, discoid lupus erythematosus, pemphigus, pemphigoid,epidermolysis bullosa urticaria, angioedema, vasculitides, toxicerythemas, cutaneous eosinophilias, alopecia greata, male-patternbaldness, Sweet's syndrome, Weber-Christian syndrome, erythemamultiforme, cellulitis, panniculitis, cutaneous lymphomas, non-melanomaskin cancer and other dysplastic lesions; blepharitis conjunctivitis,especially allergic conjunctivitis, anterior and posterior uveitis,choroiditis, autoimmune, degenerative or inflammatory disordersaffecting the retina, ophthalmitis; bronchitis, including infectious andeosinophilic bronchitis, emphysema, bronchiectasis, farmer's lung,hypersensitivity pneumonitis, idiopathic interstitial pneumonias,complications of lung transplantation, vasculitic and thromboticdisorders of the lung vasculature, pulmonary hypertension, foodallergies, gingivitis, glossitis, periodontitis, oesophagitis includingreflux, eosinophilic gastroenteritis, proctitis, pruris ani, celiacdisease, food-related allergies, inflammatory bowel disease, ulcerativecolitis and Crohn's disease, mastocytosis and also other CRTH2-mediateddiseases, for example autoimmune diseases such as hyper IgE syndrome,Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetesmellitus, idiopathic thrombocytopaenic purpura, eosinophilic paschiitis,antiphospholipid syndrome and systemic lupus erythematosus, AIDS,leprosy, Sezary syndrome, paraneoplastic syndrome, mixed andundifferentiated connective tissue diseases, inflammatory myopathiesincluding dermatomyositis and polymyositis, polymalgia rheumatica,juvenile arthritis, rheumatic fever, vasculitides including giant cellarteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritisnodosa, microscopic polyarteritis, temporal arteritis, myastheniagravis, acute and chronic pain, neuropathic pain syndromes, central andperipheral nervous system complications of malignant, infectious orautoimmune processes, low back pain, familial Mediterranean Fever,Muckle-Wells syndrome, Familial Hibernian fever, Kikuchi disease,psoriasis, acne, multiple sclerosis, allograft rejection, reperfusioninjury, chronic obstructive pulmonary disease, as well as rheumatoidarthritis, Still's disease, ankylosing spondylitis, reactive arthritis,undifferentiated spondarthropathy, psoriatic arthritis, septic arthritisand other infection-related arthopathies and bone disorders andosteoarthritis; acute and chronic crystal-induced synovitis includingurate gout, calcium pyrophosphate deposition disease, calcium paptiterelated tendon syndrome and synovial inflammation, Behcet's disease,primary and secondary Sjogren's syndrome systemic sclerosis and limitedscleroderma; hepatitis, cirrhosis of the liver, cholecystitis,pancreatitis, nephritis, nephritic syndrome, cystitis and Runner'sulcer, acute and chronic urethritis, prostatitis, epididymitis,oophoritis, salpingitis, vulvo-vaginitis, Peyronie's disease, erectiledysfunction, Alzheimer's disease and other dementing disorders;pericarditis, myocarditis, inflammatory and auto-immune cardiomyopathiesincluding myocardial sarcoid, ischaemic reperfusion injuries,endocarditis, valvulitis, aortitis, phlebitis, thrombosis, treatment ofcommon cancers and fibrotic conditions such as idiopathic pulmonaryfibrosis including cryptogenic fibrosing alveolitis, keloids, excessivefibrotic scarring/adhesions post surgery, liver fibrosis including thatassociated with hepatitis B and C, uterine fibroids, sarcoidosis,including neurosarcoidosis, scleroderma, kidney fibrosis resulting fromdiabetes, fibrosis associated with RA, atherosclerosis, includingcerebral atherosclerosis, vasculitis, myocardial fibrosis resulting frommyocardial infarction, cystic fibrosis, restenosis, systemic sclerosis,Dupuytren's disease, fibrosis complicating anti-neoplastic therapy andchronic infection including tuberculosis and aspergillosis and otherfungal infections, and CNS fibrosis following stroke. The compounds arealso of use in the promotion of healing without fibrotic scarring.

The compounds are particularly effective when used for the treatment orprevention of allergic asthma, perennial allergic rhinitis, seasonalallergic rhinitis, atopic dermatitis, contact hypersensitivity(including contact dermatitis), conjunctivitis, especially allergicconjunctivitis, vernal keratoconjunctivitis and atopickeratoconjunctivitis, eosinophilic bronchitis, food allergies,eosinophilic gastroenteritis, inflammatory bowel disease, ulcerativecolitis and Crohn's disease, mastocytosis and also other PGD2-mediateddiseases, for example autoimmune diseases such as hyper IgE syndrome andsystemic lupus erythematus, psoriasis, acne, multiple sclerosis,allograft rejection, reperfusion injury, chronic obstructive pulmonarydisease, as well as rheumatoid arthritis, psoriatic arthritis,osteoarthritis and fibrotic diseases caused/exacerbated by Th2 immuneresponses, for example idiopathic pulmonary fibrosis and hypertrophicscars.

The compounds of general formula (I) or (II) must be formulated in anappropriate manner depending upon the diseases or conditions they arerequired to treat.

Therefore, in a further aspect of the invention there is provided apharmaceutical composition comprising a compound of general formula (I)or (II) together with a pharmaceutical excipient or carrier. Otheractive materials may also be present, as may be considered appropriateor advisable for the disease or condition being treated or prevented.

The carrier, or, if more than one be present, each of the carriers, mustbe acceptable in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipient.

The formulations include those suitable for oral, rectal, nasal,bronchial (inhaled), topical (including eye drops, buccal andsublingual), vaginal or parenteral (including subcutaneous,intramuscular, intravenous and intradermal) administration and may beprepared by any methods well known in the art of pharmacy.

The route of administration will depend upon the condition to be treatedbut preferred compositions are formulated for oral, nasal, bronchial ortopical administration.

The composition may be prepared by bringing into association the abovedefined active agent with the carrier. In general, the formulations areprepared by uniformly and intimately bringing into association theactive agent with liquid carriers or finely divided solid carriers orboth, and then if necessary shaping the product. The invention extendsto methods for preparing a pharmaceutical composition comprisingbringing a compound of general formula (I) or (II) in conjunction orassociation with a pharmaceutically or veterinarily acceptable carrieror vehicle.

Formulations for oral administration in the present invention may bepresented as: discrete units such as capsules, sachets or tablets eachcontaining a predetermined amount of the active agent; as a powder orgranules; as a solution or a suspension of the active agent in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water in oil liquid emulsion; or as a bolus etc.

-   -   For compositions for oral administration (e.g. tablets and        capsules), the term “acceptable carrier” includes vehicles such        as common excipients e.g. binding agents, for example syrup,        acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone        (Povidone), methylcellulose, ethylcellulose, sodium        carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose        and starch; fillers and carriers, for example corn starch,        gelatin, lactose, sucrose, microcrystalline cellulose, kaolin,        mannitol, dicalcium phosphate, sodium chloride and alginic acid;        and lubricants such as magnesium stearate, sodium stearate and        other metallic stearates, glycerol stearate, stearic acid,        silicone fluid, talc waxes, oils and colloidal silica.        Flavouring agents such as peppermint, oil of wintergreen, cherry        flavouring and the like can also be used. It may be desirable to        add a colouring agent to make the dosage form readily        identifiable. Tablets may also be coated by methods well known        in the art.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active agent in a free flowingform such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, preservative, surface-active or dispersingagent. Moulded tablets may be made by moulding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.The tablets may optionally be coated or scored and may be formulated soas to provide slow or controlled release of the active agent.

Other formulations suitable for oral administration include lozengescomprising the active agent in a flavoured base, usually sucrose andacacia or tragacanth; pastilles comprising the active agent in an inertbase such as gelatin and glycerin, or sucrose and acacia; andmouthwashes comprising the active agent in a suitable liquid carrier.

-   -   For topical application to the skin, compounds of general        formula (I) or (II) may be made up into a cream, ointment,        jelly, solution or suspension etc. Cream or ointment        formulations that may be used for the drug are conventional        formulations well known in the art, for example, as described in        standard text books of pharmaceutics such as the British        Pharmacopoeia.

Compounds of general formula (I) or (II) may be used for the treatmentof the respiratory tract by nasal, bronchial or buccal administrationof, for example, aerosols or sprays which can disperse thepharmacological active ingredient in the form of a powder or in the formof drops of a solution or suspension. Pharmaceutical compositions withpowder-dispersing properties usually contain, in addition to the activeingredient, a liquid propellant with a boiling point below roomtemperature and, if desired, adjuncts, such as liquid or solid non-ionicor anionic surfactants and/or diluents. Pharmaceutical compositions inwhich the pharmacological active ingredient is in solution contain, inaddition to this, a suitable propellant, and furthermore, if necessary,an additional solvent and/or a stabiliser. Instead of the propellant,compressed air can also be used, it being possible for this to beproduced as required by means of a suitable compression and expansiondevice.

Parenteral formulations will generally be sterile.

Typically, the dose of the compound will be about 0.01 to 100 mg/kg; soas to maintain the concentration of drug in the plasma at aconcentration effective to inhibit PGD₂ at the CRTH2 receptor. Theprecise amount of a compound of general formula (I) or (II) which istherapeutically effective, and the route by which such compound is bestadministered, is readily determined by one of ordinary skill in the artby comparing the blood level of the agent to the concentration requiredto have a therapeutic effect.

Compounds of general formula (I) or (II) may be used in combination withone or more active agents which are useful in the treatment of thediseases and conditions listed above, although these active agents arenot necessarily inhibitors of PGD₂ at the CRTH2 receptor.

Therefore, the pharmaceutical composition described above mayadditionally contain one or more of these active agents.

There is also provided the use of a compound of general formula (I) or(II) in the preparation of an agent for the treatment of diseases andconditions mediated by CRTH2 receptor agonists, especially PGD₂, whereinthe agent also comprises an additional active agent useful for thetreatment of the same diseases and conditions.

These additional active agents may be other CRTH2 receptor antagonistsor may have a completely different mode of action. They include existingtherapies for allergic and other inflammatory diseases including:

-   Suplatast tosylate and similar compounds;-   β2 adrenoreceptor agonists such as metaproterenol, isoproterenol,    isoprenaline, albuterol, salbutamol, formoterol, salmeterol,    indacaterol, terbutaline, orciprenaline, bitolterol mesylate and    pirbuterol or methylxanthines such as theophylline and    aminophylline, mast cell stabilisers such as sodium cromoglycate or    muscarinic receptor antagonists such as tiotropium;-   antihistamines, for example histamine H₁ receptor antagonists such    as loratadine, cetirizine, desloratadine, levocetirizine,    fexofenadine, astemizole, azelastine and chlorpheniramine or H₄    receptor antagonists;-   α₁ and α₂ adrenoreceptor agonists such as propylhexedrine    phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline    hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline    hydrochloride, xylometazoline hydrochloride and ethylnorepinephrine    hydrochloride;-   modulators of chemokine receptor function, for example CCR1, CCR2,    CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and    CCR11 (for the C—C family) or CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5    (for the C—X—C family) and CX₃CR1 for the C—X₃—C family;-   Leukotriene antagonists such as montelukast and zafirlukast    leukotriene biosynthesis inhibitors such as 5-lipoxygenase    inhibitors or 5-lipoxygenase activating protein (FLAP) inhibitors    such as zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79175,    N-(5-substituted)-thiophene-2-alkylsolfonamides,    2,6-di-tert-butylphenol hydrazones, methoxytetrahydropyrans such as    ZD2138, SB-210661, pyridinyl-substituted-2-cyanonaphthalene    compounds such as L-739010, 2-cyanoquinoline compounds such as    L-746,530, indole and quinoline compounds such as MK-591, MK-886 and    BAY x 1005;-   Phosphdiesterase inhibitors, including PDE4 inhibitors such as    roflumilast;-   anti-IgE antibody therapies such as omalizumab;-   anti-infectives such as fusidic acid (particularly for the treatment    of atopic dermatitis);-   anti-fungals such as clotrimazole (particularly for the treatment of    atopic dermatitis); immunosuppressants such as tacrolimus and    particularly pimecrolimus in the case of inflammatory skin disease    or alternatively FK-506, rapamycin, cyclosporine, azathioprine or    methotrexate;-   Immunotherapy agents including allergen immunotherapy such as    Grazax;-   corticosteroids such as prednisone, prednisolone, flunisolide,    triamcinolone acetonide, beclomethasone dipropionate, budesonide,    fluticasone propionate mometasone furoate and fluticasone furoate    drugs which promote Th1 cytokine response such as interferons, TNF    or GM-CSF.-   CRTH2 antagonists may also be combined with therapies that are in    development for inflammatory indications including:-   other antagonists of PGD₂ acting at other receptors such as DP    antagonists; drugs that modulate cytokine production such as    inhibitors of TNFα converting enzyme (TACE) anti-TNF monoclonal    antibodies, TNF receptor immunoglobulin molecules, inhibitors of    other TNF isoforms, non-selective COX-1/COX-2 inhibitors such as    piroxicam, diclofenac, propionic acids such as naproxen,    flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as    mefanamic acid, indomethacin, sulindac and apazone, pyrazolones such    as phenylbutazone, salicilates such as aspirin; COX-2 inhibitors    such as meloxicam, celecoxib, fofecoxib, valdecoxib and etoricoxib,    low dose methotrexate, lefunomide, ciclesonide, hydroxychloroquine,    d-penicillamine, auranofin or parenteral or oral gold;-   drugs that modulate the activity of Th2 cytokines IL-4 and IL-5 such    as blocking monoclonal antibodies and soluble receptors;-   PPAR-γ agonists such as rosiglitazone; or with anti-RSV antibodies    such as Synagis (palivizumab) and agents that may be used to treat    rhinovirus infection in the future e.g. interferon-alpha,    interferon-beta or other interferons.

In yet a further aspect of the invention, there is provided a productcomprising a compound of general formula (I) or (II) and one or more ofthe agents listed above as a combined preparation for simultaneous,separate or sequential use in the treatment of a disease or conditionmediated by the action of PGD₂ at the CRTH2 receptor.

In yet another aspect of the invention, there is provided a kit for thetreatment of a disease or condition mediated by the action of PGD₂ atthe CRTH2 receptor comprising a first container comprising a compound ofgeneral formula (I) or (II) and a second container comprising one ormore of the active agents listed above.

The invention will now be described in greater detail with reference tothe following non limiting examples.

In Example 1, the ¹H NMR spectra were obtained using a Bruker Advance IIspectrometer operating at 300 MHz. All signals were referenced relativeto residual protic solvent.

In Examples 2 and 3, NMR spectra were collected on a Jeol JNM-GSXspectrometer operating at 400 MHz for ¹H NMR data acquisition and 100MHz for ¹³C NMR data acquisition.

In Example 1, HPLC-CAD-MS was performed on a Gilson 321 HPLC withdetection performed by a ESA Corona CAD and a Finnigan AQA massspectrometer operating in positive-ion electrospray ionisation mode. TheHPLC column was a Phenomenex Gemini C18 50×4.6 mm 3μ, with a mobilephase gradient between 100% 0.1% formic acid in water and 100% 0.1%formic acid in acetonitrile run over 2.5 minutes, with a total run timeof 6.5 minutes. In some cases MS only was obtained using the instrumentdescribed above.

In Examples 2 and 3, HPLC was performed on an Agilent 1050 HPLC withdetection performed by UV at 220 nm. The HPLC column was a YMC-Pack,ODS-A 150×4.6 mm 5μ, with a mobile phase gradient between 100%-0.01%trifluoracetic acid in water and 100%-0.01% trifluoracetic acid inacetonitrile run over 16 minutes, with a total run time of 21 minutes.

EXAMPLE 1 Preparation of(3-{[2-(benzenesulfonyl)pyridin-3-yl]methyl}-5-fluoro-2-methylindol-1-yl)-aceticacid (Compound 1) 2-(Benzenesulfonyl)isonicotinaldehyde

To a stirred suspension of benzenesulfinic acid sodium salt (9.36 g,0.057 mol) in DMSO (45 ml), was added 2-fluoro-3-pyridinecarboxaldehyde(5.20 ml, 0.052 mol). The resulting mixture was stirred at 100° C. for94 hours. After cooling to room temperature, the reaction mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated and the aqueous further extracted with ethyl acetate (3×150ml). The combined organic extracts were washed with water (100 ml) andbrine (100 ml), dried over anhydrous MgSO₄, filtered and evaporated. Theresulting solid was purified by column chromatography eluting with ethylacetate:hexanes 0:100 to 60:40 v/v to afford 6.56 g (51%) of the titlecompound (LCMS RT=5.63 min, MH⁺ 248).

¹H NMR (DMSO): 10.89 (1H, d, J 0.68 Hz), 8.82 (1H, dd, J 1.7, 4.7 Hz),8.32 (1H, dd, J 1.7, 7.9 Hz), 8.08-8.02 (2H, m), 7.85 (1H, dd, J 7.9,0.7 Hz), 7.81 (1H, dt, J 1.3, 7.5 Hz), 7.73-7.65 (2H, m).

[3-(2-Benzenesulfonyl-pyridin-3-ylmethyl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid ethyl ester

A solution of (5-fluoro-2-methyl-indol-1-yl)-acetic acid ethyl ester(0.95 g, 4.04 mmol), prepared as described in Example 1 ofWO/2006/092579, and 2-(benzenesulfonyl)isonicotinaldehyde (1.0 g, 4.04mmol) in dry dichloromethane (45 ml) was added slowly over 5 minutes toa stirred solution of TMSOTf (1.46 ml, 8.08 mmol) in dry dichloromethane(12.5 ml) cooled to 0° C. under N₂. This mixture was stirred for 15minutes and triethylsilane (1.94 ml, 12.12 mmol) was added in oneportion. The reaction mixture was stirred for 2 h 30 minutes, warmed toroom temperature, and quenched by the slow addition of saturated aqueousNaHCO₃ (10 ml). The resulting biphasic mixture was extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous MgSO₄, filtered and evaporated. The resulting solidwas purified by column chromatography eluting with ethyl acetate:hexanes0:100 to 60:40 v/v to afford 1.21 g (64%) of the title compound (LCMSRT=6.63 min, MH⁺ 466.8).

¹H NMR (CDCl₃): 8.38 (1H, dd, J 1.6, 4.5 Hz), 8.14-8.07 (2H, m), 7.67(3H, ddt, J 1.3, 27.7, 7.4 Hz), 7.40-7.34 (1H, m), 7.22 (1H, dd, J 4.6,7.9 Hz), 7.12 (1H, dd, J 4.2, 8.9 Hz), 6.90 (1H, dt, J 2.5, 9.0 Hz),6.72 (1H, dd, J 2.4, 9.5 Hz), 4.82 (2H, s), 4.62 (2H, s), 4.24 (2H, q, J7.2 Hz), 2.30 (3H, s), 1.29 (3H, t, J 7.2 Hz).

(3-{[2-(Benzenesulfonyl)pyridin-3-yl]methyl}-5-fluoro-2-methylindol-1-yl)-aceticacid (Compound 1)

To a stirred solution of[3-(2-benzenesulfonyl-pyridin-3-ylmethyl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid ethyl ester (1.20 g, 2.56 mmol) in THF (26 ml) was added a solutionof potassium hydroxide (0.43 g, 7.68 mmol) in water (9 ml). Theresulting solution was stirred at room temperature for 3.5 h. THF wasremoved in vacuo and the remaining aqueous layer was acidified withaqueous HCl (0.1 M, 25 ml). The product was collected by filtration,washed with water and dried in vacuo to afford 1.12 g (100%) of thetitle compound (LCMS RT=4.58 min, M⁺−H 437.2).

¹H NMR (DMSO): 8.41-8.27 (1H, m), 8.06-7.91 (2H, m), 7.84-7.62 (3H, m),7.50-7.31 (3H, m), 6.93-6.78 (2H, m), 4.99 (2H, s), 4.55 (2H, s), 2.27(3H, s).

EXAMPLE 2 Preparation of[5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-aceticacid (Compound 2) 2-(4-Fluorobenzenesulfonyl)-pyridine-3-carboxaldehyde

2-Chloro-3-pyridine-3-carboxaldehyde (4.04 g, 2.86 mmol) and4-fluorobenzenesulfinic acid sodium salt (5.73 g, 3.14 mmol) weredissolved in DMSO (100 ml) and the mixture was heated at 100° C. for 72h under nitrogen. Upon cooling to ambient the mixture was diluted withwater (500 ml) and extracted with EtOAc (3×). The combined organics werewashed with water, brine, dried (MgSO₄) and evaporated to dryness toafford 7.89 g of crude product. The crude compound was pre-absorbed ontosilica and purified by dry pad suction column chromatography, elutingwith heptane using an EtOAc gradient, to afford 4.14 g (41%) of thedesired product as a yellow solid (plates) (MP=131-131.3° C.; IR=1691cm⁻¹; HPLC=7.21 min >99%).

¹H NMR (400 MHz; CDCl₃): 7.23-7.29 (2H, m) 7.60 (1H, dd) 8.05-8.10 (2H,m) 8.37 (2H, dd) 8.67 (1H, dd) 11.1 (1H, s).

¹³C NMR (100 MHz, CDCl₃): 116.6 (d) 116.8 (d) 127.3 (d) 130.7 (s) 132.6(d) 134.0 (s) 137.9 (d) 152.5 (s) 159.7 (s) 165.1 (s) 167.7 (s) 188.5(d).

[5-Fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-aceticacid ethyl ester

A solution of (5-fluoro-2-methyl-indol-1-yl)-acetic acid ethyl ester(1.0 g, 4.4 mmol) and2-(4-fluorobenzenesulfonyl)-pyridine-3-carboxaldehyde (1.13 g, 4.3 mmol)in dry DCM (50 ml) was added over 5-10 min to a stirred solution ofTMSOTf in dry DCM (15 ml) at 0° C. The mixture was aged for 15 minbefore the addition of neat triethylsilane (2.05 ml, 12.8 mmol) in oneportion. The mixture was stirred for a further 15 h and allowed to warmup to ambient. The reaction was quenched by the drop wise addition ofsaturated NaHCO₃ solution (10 ml) and the biphasic mixture extractedwith DCM (2×50 ml). The combined organics were washed with brine (50 ml)then dried (MgSO₄) and evaporated to dryness. The reaction was repeatedon an identical scale and the two crude materials were purifiedseparately. The crude reaction materials were purified by columnchromatography using heptane and an ethyl acetate gradient to afford0.90 g (43%) and 1.50 g (72%) of the desired compound as a pale purplesolid and a brown solid respectively of differing purities (96.0% and94.5% by HPLC) (MP=150.5-151.5° C., IR=1751 cm⁻¹; HPLC=12.24 min).

¹H NMR (400 MHz; CDCl₃): 1.26 (3H, t) 2.29 (3H, s) 4.22 (2H, q) 4.62(2H, s) 4.80 (2H, s) 6.79 (1H, dd) 6.86 (1H, ddd) 7.10 (1H, dd) 7.19(1H, dd) 7.23-7.28 (2H, m) 7.36 (1H, dd) 8.05-8.11 (2H, m) 8.29 (1H,dd).

¹³C NMR (100 MHz, CDCl₃): 10.4 (q) 14.2 (q) 25.3 (t) 45.2 (t) 61.9 (t)103.4 (d) 103.6 (d) 108.0 (s) 108.1 (s) 109.1 (d) 109.2 (d) 109.5 (d)109.8 (d) 116.2 (d) 116.4 (d) 127.0 (d) 128.5 (s) 128.6 (s) 132.2 (d)132.3 (d) 133.3 (s) 135.1 (s) 136.4 (s) 136.6 (s) 139.4 (d) 146.2 (d)156.2 (s) 157.0 (s) 159.4 (s) 164.7 (s) 167.3 (s) 168.6 (s).

[5-Fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-aceticacid (Compound 2)

KOH (0.34 g, 5.94 mmol) was dissolved in water (7 ml) and added to avigorously stirred solution of[5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-aceticacid ethyl ester (0.96 g, 1.98 mmol) in THF (21 ml) under nitrogen atambient. The reaction was monitored by TLC and LCMS. After 2 h thesolvent was removed in vacuo before adjusting the pH to 1.5 using 0.1 MHCl solution. The precipitate was stirred vigorously for 15 min beforebeing isolated by suction filtration. The collected solid was washedwith water and then MTBE, pulled dry in air and then dried in vacuo at50° C. to afford 870 mg (97%) of the product as a pink solid(MP=125-126° C.; IR=1729 cm⁻¹; HPLC=10.80 min 99.3%).

¹H NMR (400 MHz; DMSO): 2.29 (3H, s) 4.56 (2H, s) 4.97 (2H, s) 6.85-6.91(2H, m) 7.37-7.7.45 (2H, m) 7.47 (1H, dd) 7.51-7.57 (2H, m) 8.06-8.15(2H, m) 8.36 (1H, dd).

¹³C NMR (100 MHz, DMSO): 10.5 (q) 25.0 (t) 45.5 (t) 102.7 (d) 102.9 (d)107.7 (s) 107.8 (s) 108.8 (d) 109.1 (d) 110.9 (d) 111.0 (d) 117.1 (d)117.3 (d) 128.1 (d) 128.2 (d) 128.3 (d) 132.7 (d) 132.8 (d) 133.8 (d)135.5 (s) 136.8 (s) 138.1 (s) 140.4 (d) 147.0 (d) 155.9 (s) 156.6 (s)158.9 (s) 164.6 (s) 167.1 (s) 171.1 (s).

EXAMPLE 3 Preparation of[3-({2-[(4-chlorobenzene)sulfonyl]pyridin-3-yl}methyl)-5-fluoro-2-methylindol-1-yl]-aceticacid (Compound 3) 2-(4-Chlorobenzenesulfonyl)-pyridine-3-carboxaldehyde

2-Chloro-3-pyridinecarboxaldehyde (5.0 g, 35.0 mmol) and4-chlorobenzenesulfinic acid sodium salt (7.75 g, 38.8 mmol) weredissolved in DMSO (120 ml) and the mixture was heated at 100° C. for 72h under nitrogen. Upon cooling to ambient the mixture was diluted withwater (500 ml) and extracted with EtOAc (3×). The combined organics werewashed with water, brine, dried (MgSO₄) and evaporated to dryness toafford 8.1 g of crude material. The crude compound was pre-absorbed ontosilica and purified by dry pad suction column chromatography, elutingwith heptane using an EtOAc gradient, to afford 4.62 g (61%) of thedesired product as a white powdery solid (MP=100.5-101° C.; IR=1698cm⁻¹; HPLC=8.00 min >99%).

¹H NMR (400 MHz; CDCl₃): 7.56 (1H, dd) 7.60 (114, dd) 7.99 (1H, dd) 8.38(1H, dd) 8.67 (1H, dd) 11.1 (1H, s).

¹³C NMR (100 MHz, CDCl₃): 127.3 (d) 129.6 (d) 130.8 (s) 131.1 (d) 136.5(s) 138.0 (d) 141.4 (s) 152.5 (d) 159.5 (s) 188.4 (d).

[3-({2-[4-Chlorobenzene)sulfonyl]pyridin-3-yl}methyl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid ethyl ester

A solution of (5-fluoro-2-methyl-indol-1-yl)-acetic acid ethyl ester(1.0 g, 4.25 mmol) and2-(4-chlorobenzenesulfonyl)-pyridine-3-carboxaldehyde (1.19 g, 4.22mmol) in dry DCM (50 ml) was added over 5-10 min to a stirred solutionof TMSOTf in dry DCM (15 ml) at 0° C. The mixture was aged for 15 minbefore the addition of neat triethylsilane (2.05 ml, 12.7 mmol) in oneportion. The mixture was stirred for a further 15 h and allowed to warmup to ambient. The reaction was quenched by the drop wise addition ofsaturated NaHCO₃ solution (10 ml) and the biphasic mixture extractedwith DCM (2×50 ml). The combined organics were washed with brine (50 ml)then dried (MgSO₄) and evaporated to dryness. The reaction was repeatedon an identical scale and the two crude products were combined. Thecrude reaction material was purified by column chromatography usingheptane and an ethyl acetate gradient to afford 1.80 g (42%) of thedesired compound as a pale orange solid (MP=124.6-124.9° C.; IR=1741cm⁻¹; HPLC=12.75 min 97.3%).

¹H NMR (400 MHz; CDCl₃): 1.26 (3H, t) 2.29 (3H, s) 4.20 (2H, q) 4.62(2H, s) 4.80 (2H, s) 6.80 (1H, dd) 6.87 (1H, ddd) 7.10 (1H, dd) 7.19(1H, dd) 7.37 (1H, dd) 7.54 (2H, dd) 8.00 (2H, dd) 8.28 (1H, dd).

¹³C NMR (100 MHz, CDCl₃): 10.4 (q) 14.3 (q) 25.3 (t) 45.2 (t) 61.9 (t)103.4 (d) 103.6 (d) 108.0 (s) 108.1 (s) 109.2 (d) 109.2 (d) 109.5 (d)109.8 (d) 127.0 (d) 128.5 (s) 128.6 (s) 129.3 (d) 130.8 (d) 133.3 (s)136.4 (s) 136.6 (s) 137.6 (s) 139.4 (d) 140.5 (s) 146.2 (d) 156.1 (s)157.0 (s) 159.4 (s) 168.6 (s).

[3-({2-[(4-Chlorobenzene)sulfonyl]pyridin-3-yl}methyl)-5-fluoro-2-methylindol-1-yl]-aceticacid (Compound 3)

KOH (0.60 g, 10.7 mmol) dissolved in water (14 ml) was added to avigorously stirred solution of[3-({2-[(4-chlorobenzene)sulfonyl]pyridin-3-yl}methyl)-5-fluoro-2-methylindol-1-yl]-aceticacid ethyl ester (1.17 g, 3.49 mmol) in THF (40 ml) under nitrogen atambient. The reaction was monitored by TLC and LCMS. After 2 h thesolvent was removed in vacuo before adjusting the pH to 1.5 using 0.1MHCl solution. The precipitate was stirred vigorously for 15 min beforebeing isolated by suction filtration. The collected solid was washedwith water and then MTBE, pulled dry in air and then dried in vacuo at50° C. to afford 1.31 g (78%) of the title compound as a pink solid(MP=125.2-126° C.; IR=1729 cm⁻¹; HPLC=11.37 min >99%).

¹H NMR (400 MHz; DMSO): 2.29 (3H, s) 4.56 (2H, s) 4.96 (2H, s) 6.85-6.91(2H, m) 7.39 (1H, dd) 7.44 (1H, dd) 7.49 (1H, dd) 7.76-7.79 (2H, m)8.00-8.8.03 (2H, m) 8.36 (1H, dd).

¹³C NMR (100 MHz, DMSO): 10.5 (q) 25.0 (t) 45.6 (t) 102.7 (d) 102.9 (d)107.6 (s) 107.7 (s) 108.8 (d) 109.0 (d) 110.9 (d) 111.0 (d) 128.1 (d)130.0 (d) 131.4 (d) 133.9 (d) 136.9 (s) 138.1 (d) 139.8 (s) 140.5 (s)147.1 (d) 155.7 (s) 156.5 (s) 158.9 (s) 171.1 (s).

In the following examples, Compounds 1 to 3 were tested against thefollowing comparator compounds:

Cpd. Name Structure A [3-(4-Methylsulfonyl-benzyl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid

B [3-(3-Benzenesulfonyl-pyridin-4-ylmethyl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid

C [3-(3-Benzenesulfonyl-pyridin-2-ylmethyl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid

D [3-(1-Benzenesulfonyl-1H-pyrrol-2-ylmethyl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid

E 5-Fluoro-2-methyl-3-(pyridin-3-ylmethyl)- indol-1-yl)-acetic acid

Compounds B, C and E were prepared using an analogous method to thatused for Compound 1. Compound A is Compound 17 of WO 2005/044260 and amethod for the preparation of this compound is set out in Example 1 ofthat document. Compound D is Compound 1 of WO 2006/095183 and a methodfor its preparation is set out in Example 1 of that document.

EXAMPLE 4 Measurement of CRTH2 Antagonist Activity

Materials and Methods

Materials

Mono-polyresolving medium was obtained from Dainippon Pharmaceuticals(Osaka, Japan). Macs anti-CD16 microbeads were from Miltenyi biotec(Bisley, Surrey). ChemoTx plates were purchased from Neuroprobe(Gaithersburg, Md.). Poly-D-lysine coated 96-well plates were obtainedfrom Greiner (Gloucestershire, UK). [³H]PGD₂ was from AmershamBiosciences (Buckinghamshire, UK). [³H]SQ29548 was purchased from PerkinElmer Life Sciences (Buckinghamshire, UK). All other reagents wereobtained from Sigma-Aldrich (Dorset, UK), unless otherwise stated.

Methods

Cell Culture

Chinese Hamster Ovary cells were transfected with CRTH2 or DP receptors(CHO/CRTH2 and CHO/DP) and were maintained in culture in a humidifiedatmosphere at 37° C. (5% CO₂) in Minimum Essential Medium (MEM)supplemented with 10% foetal bovine serum, 2 mM glutamine, and 1 mg ml⁻¹active G418. The cells were passaged every 2-3 days. For radioligandbinding assay, cells were prepared in triple-layer flasks or in 175 cm²square flasks (for membrane preparation).

Preparation of Cell Membranes

Membranes were prepared either from CHO/CRTH2 and CHO/DP cells, or fromplatelets (as a source of TP receptors). CHO cells grown to confluencywere washed with PBS and detached using a Versene solution (15 ml perflask). When the cells were grown in 175 cm² square flask, they werecollected by scrapping in PBS. The cell suspensions were centrifuged(1,700 rpm, 10 min, 4° C.) and resuspended in 15 ml of buffer (1×HBSS,supplemented with 10 mM HEPES, pH 7.3). Cell suspensions were thenhomogenised using an Ultra Turrax at setting 4-6 for 20 s. Thehomogenate was centrifuged at 1,700 rpm for 10 min and the supernatantwas collected and centrifuged at 20,000 rpm for 1 h at 4° C. Theresulting pellet was resuspended in buffer and stored at −80° C. inaliquots of 200-500 μl. The protein concentration was determined by themethod of Bradford (1976), using bovine serum albumin as standard. Theplatelets were washed by centrifugation at 600×g for 10 min andresuspended in ice-cold assay buffer (10 mM Tris-HCl, pH 7.4, 5 mMGlucose, 120 mM NaCl, 10 μM indomethacin) and directly centrifuged at20,000 rpm for 30 min at 4° C. The resulting pellet was treated asdescribed above.

Radioligand Binding Assays

[³H]PGD₂ (160 Ci/mmol) binding experiments were performed on membranesprepared as described above. Assays were performed in a final volume of100 μl of buffer (1×HBSS/HEPES 10 mM, pH 7.3). Cell membranes (15 μg)were preincubated at room temperature with varying concentration ofcompeting ligand for 15 min. [³H]PGD₂ was then added and the incubationcontinued for a further one hour at room temperature. The reaction wasterminated by the addition of 200 μl ice-cold assay buffer to each well,followed by rapid filtration through Whatman GF/B glass fibre filtersusing a Unifilter Cell harvester (PerkinElmer Life Sciences) and sixwashes of 300 μl of ice-cold buffer. The Unifilter plates were dried atroom temperature for at least 1 h and the radioactivity retained on thefilters was determined on a Beta Trilux counter (PerkinElmer LifeSciences), following addition of 40 μl of Optiphase Hi-Safe 3 (Wallac)liquid scintillation. Non specific binding was defined in the presenceof 10 μM unlabelled PGD₂. Assays were performed in duplicate.

The results of the radioligand binding experiments to the CRTH2 areshown in Table 1.

TABLE 1 Radioligand binding data (K_(i) on CRTH2 Receptor). CompoundsK_(i) (nM) Compound 1 2 Compound 2 2 Compound 3 7 Compound A 7 CompoundB 1 Compound C 979 Compound D 1 Compound E 258

Compounds C and E bind only very weakly to the CRTH2 receptor and weretherefore not tested further.

EXAMPLE 5 Human Whole Blood Eosinophil Shape Change Assay

Compounds 1-3 were assayed for their effect on PGD2 induced eosinophilshape change and were compared with Comparator Compounds A, B and D.

Methods

Shape Change Assay in Whole Blood

Compounds (1 μl, 200× final concentration) were added directly to 200 μlwhole blood, mixed well and incubated for 15 min, 37° C., 5% CO₂. Afterthis time, cell shape was fixed by addition of 300 μl Cytofix™ buffer(BD Biosciences), 15 min on ice. 10 ml RBC lysis buffer was added to thefixed cells, incubated 5 min, at room temperature and centrifuged, 300×gfor 5 min. Supernatant (containing lysed red cells) was removed and thelysis step was repeated. Leukocytes were resuspended in 250 μl RPMI/10%FCS and shape change analysed by FACS. Eosinophils were gated out basedon their autofluorescence and 2000 eosinophil events were counted persample. Data were analysed in triplicate.

The results for the eosinophil shape change assay are shown in Table 2.

TABLE 2 IC₅₀ Values for the Effect of Test Compounds on 10 nM PGD₂-induced Eosinophil Shape Change in human whole blood Compound Value (nM)1 9 2 2.5 3 10 A 8 B 34 D 8

Compounds which are most suitable for use as pharmaceutical agents havean IC₅₀ value in the eosinophil shape change test of between about 1 and10 nM. Therefore, although Compound B binds specifically to the CRTH2receptor (Table 1), it is not a particularly potent CRTH2 antagonistunder physiological conditions.

It is particularly worthy of note that the comparator compounds closestin structure to that of Compound 1 are Compounds B and C. Of these,Compound C does not bind specifically to the CRTH2 receptor and CompoundB is much less potent than Compound 1.

EXAMPLE 6 Microsomal Stability

The microsomal stability of the test compounds was determined by thefollowing method.

1 micromolar test compound was incubated with human liver microsomes(total protein concentration 0.3 mg/ml) for 60 min. The percentage ofthe test compound remaining in the sample after 1 hour was measured inorder to determine the rate of metabolism of test compound. The resultsare shown in Table 3, which gives the results for two experiments andthe mean value obtained.

TABLE 3 Microsomal Stability Test Results Mean Parent Compound TestConcentration (M) remaining (%) 1 1 × 10⁻⁶ 96 2 1 × 10⁻⁶ 98 B 1 × 10⁻⁶69 C 1 × 10⁻⁶ 90 D 1 × 10⁻⁶ 24

The results presented in Table 3 demonstrate that after 120 minutes, 96%of Compound 1 and 98% of compound 2 is unmetabolised in human livermicrosomes. This compares with values of 69% and 90% respectively forCompounds B and C, which are regioisomers of Compound 1 and a value ofonly 24% for Compound D.

In summary therefore, the experiments described in these examplesdemonstrate that Compounds C and E do not bind strongly to the CRTH2receptor, Compound B is much less active than Compound 1 in the wholeblood eosinophil shape change assay and Compound D has low stability inhuman microsomes, which limits its utility as a pharmaceutical agent.Compounds 1 and 2 surprisingly combine the advantageous attributes ofhigh activity as CRTH2 antagonists and high stability in comparison withcompounds to which they are structurally most closely related.

Furthermore, certain of the compounds of the present invention have beenfound to demonstrate significantly improved in vivo pharmacokineticprofiles in the dog compared to compound A. The plasma half-lives forCompounds 1 and 2 were 3 and 5 hours respectively whereas Compound A hada half life of only 1 hour.

The invention claimed is:
 1. A pharmaceutical composition comprising apharmaceutical excipient or carrier and a compound of formula (II):

wherein W is chloro or fluoro; R¹ is phenyl, optionally substituted withone or more substituents, selected from halo; and R⁴ is hydrogen, C₁-C₆alkyl, C₁-C₆ alkyl substituted with aryl, aryl,(CH₂)_(m)OC(═O)C₁-C₆alkyl, ((CH₂)_(m)O)_(n)CH₂CH₂X, (CH₂)_(m)N(R⁵)₂, orCH((CH₂)_(m)O(C═O)R⁶)₂; m is 1 or 2; n is 1-4; X is OR⁵ or N(R⁵)₂; R⁵ ishydrogen or methyl; and R⁶ is C₁-C₁₈ alkyl; or a pharmaceuticallyacceptable salt thereof.
 2. The composition as claimed in claim 1,wherein W is fluoro.
 3. The composition as claimed in claim 1, whereinthe phenyl group R¹ is unsubstituted or is substituted wah a single halosubstituent.
 4. The composition as claimed in claim 3, wherein the halosubstituent is fluoro or chloro.
 5. The composition as claimed in claim4, wherein the fluoro or chloro substituent is at the 4-position of thephenyl group R¹.
 6. The composition as claimed in claim 1, wherein thecompound of formula (II) is selected from the group consisting of:(3-{[2-(Benzenesulfonyl)pyridin-3-yl]methyl}-5-fluoro-2-methylindol-1-yl)-aceticacid; [5-Fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid; and[3-({2-[(4-Chlorobenzene)sulfonyl]pyridin-3-yl}methyl)-5-fluoro-2-methylindol-1-yl]-aceticacid.
 7. The composition as claimed in claim 1, formulated for oral,rectal, nasal, bronchial, topical, vaginal, or parenteraladministration.
 8. The composition as claimed in claim 7, formulated fororal administration.
 9. The composition as claimed in claim 1, whereinthe pharmaceutical carrier is selected from the group consisting ofsyrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone,methylcellulose, ethylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, sucrose, starch, corn starch, gelatin,lactose, sucrose, microcrystalline cellulose, kaolin, mannitol,dicalcium phosphate, sodium chloride, alginic acid, magnesium stearate,sodium stearate, metallic stearates, glycerol stearate, stearic acid,silicone fluid, talc waxes, oils, and colloidal silica.
 10. A kit forthe treatment of a disease or condition mediated by the action of PGD₂at the CRTH2 receptor comprising: (a) a first container comprising acompound of formula (II):

wherein W is chloro or fluoro; R¹ is phenyl, optionally substituted withone or more substituents, selected from halo; and R⁴ is hydrogen, C₁-C₆alkyl, C₁-C₆ alkyl substituted with aryl, aryl,(CH₂)_(m)OC(═O)C₁-C₆alkyl, ((CH₂)_(m)O)_(n)CH₂CH₂X, (CH₂)_(m)N(R⁵)₂, orCH((CH₂)_(O(C═O)R) ⁶)₂; m is 1 or 2; n is 1-4; X is OR⁵ or N(R⁵)₂; R₅ ishydrogen or methyl; and R⁶ is C₁-C₁₈ alkyl; or a pharmaceuticallyacceptable salt thereof; and (b) a second container comprising anadditional active agent useful in the treatment of diseases orconditions mediated by the action of PGD₂ at the CRTH2 receptor.
 11. Thekit as claimed in claim 10, wherein the additional active agent isselected from the group consisting of other CRTH2 antagonists, Suplatasttosylate, β2 adrenoreceptor agonists, methylxanthines, mast cellstabilisers, muscarinic receptor antagonists, antihistamines, α₁ and α₂adrenoreceptor agonists, modulators of chemokine receptor function,leukotriene antagonists, leukotriene biosynthesis inhibitors,5-lipoxygenase activating protein inhibitors,N-(5-substituted)-thiophene-2-alkylsolfonamides, 2,6-di-tert-butylphenolhydrazones, methoxytetrahydropyrans,pyridinyl-substituted-2-cyanonaphthalene compounds, 2-cyanoquinolinecompounds, indole and quinoline compounds, phosphodiesterase inhibitors,anti-IgE antibody therapies, anti-infectives, anti-fungals,immunosuppressants, immunotherapy agents, corticosteroids, drugs whichpromote Th1 cytokine response, other agonists of PGD₂ acting at otherreceptors such as DP antagonists, drugs that modulate cytokineproduction, TNF receptor immunoglobulin molecules, inhibitors of otherTNF isoforms, non-selective COX-1/COX-2 inhibitors, COX-2 inhibitors,low dose methotrexate, lefunomide, ciclesonide, hydroxychloroquine,d-penicillamine, auranofin, parenteral or oral gold, drugs that modulatethe activity of Th2 cytokines IL-4 and IL-5, PPAR-γ agonists, anti-RSVantibodies, and agents that may be used to treat rhinovirus in thefuture.
 12. The kit as claimed in claim 10, wherein the compound offormula (II) is selected from the group consisting of:(3-{[2-(Benzenesulfonyl)pyridin-3-yl]methyl}-5-fluoro-2-methylindo-1-yl)-aceticacid;[5-Fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-aceticacid; and[3-({2-[(4-Chlorobenzene)sulfonyl]pyridin-3-yl}methyl)-5-fluoro-2-methylindol-1-yl]-aceticacid.